Why are Clinicians Using Biomarkers more Frequently?

The criteria to define the presence of sepsis clinical
severity are not satisfactory since the signs and symptoms of sepsis are poorly
specific and highly sensitive. Even more difficult than the diagnosis, is the
monitoring of infection response to antibiotics (Povoa 2008). Currently the
assessment of response relies on the resolution of the same criteria used in
the diagnosis, however it may not be completely reliable as some clinical and
radiologic variables can be influenced by non-infectious factors. Besides, the
observation that a prompt and structured approach of severe sepsis and septic
shock has a marked impact on prognosis urged the research on new tools of
sepsis diagnosis even further (Marshall et al. 2009).

Since the inflammatory cascade plays a central role in the
host-pathogen interaction and in the infection control mechanisms these
mediators have been successively assessed as potential biomarkers of infection.
By definition, an ideal biomarker of infection should be absent if the patient
is not infected, appear concomitantly and ideally precede the infection and
disappear with successful therapy or remain elevated if infection is refractory
to treatment (Povoa 2008). Whereas in myocardial infarction, 14 biomarkers are
suitable for its diagnosis and prognostic assessment, in the complex field of
sepsis more than 170 potential biomarkers have been studied and unfortunately
the ultimate biomarker has not yet been identified (Pierrakos et al. 2010).

What are the Questions We want to Ask a Biomarker of Sepsis?

Biomarkers are measures of molecular, biochemical or
cellular levels that represent changes in the normal physiologic status.
Biomarkers of sepsis indicate that the host has been exposed to an infectious
pathogen, bacterial, fungal, viral or parasite, as well as the magnitude of the
response to that infection.

At the bedside, clinicians are faced daily with the two
frequent dilemmas: (1) Whether a patient is infected or not and (2) If the
response to antimicrobial therapy is adequate.

In the presence of a patient with systemic inflammatory
response syndrome (SIRS), particularly if associated with organ dysfunction,
clinicians must consider the severity and site of the infection as well as the
most probable agent and likely sensitivity patterns.

In addition, clinicians need to monitor infection response
to antibiotics as well as to ascertain the duration of antibiotic therapy, thus
raising two additional questions:

1. Is the infection refractory to therapy? Should I change
the antimicrobials?

2. Is the infection cured? Can I safely stop antimicrobials?

Despite their importance, these questions are currently
those most frequently cited by clinicians as ‘impossible to answer with
absolute confidence’. Biomarkers can be useful in some of these questions but
the evaluation of their clinical performance is further complicated by the
absence of a “gold standard” for the diagnosis of sepsis (Pierrakos et al.
2010).

What are the Questions Biomarkers Can Answer?

In the last 20 years, the research of biomarkers of sepsis
has increased markedly. However, the great majority of studies evaluated their
utility just in the assessment of prognosis. Biomarkers have a limited value
methodologies, namely in inclusion and exclusion criteria, used for the
selection of patients to be evaluated and analysed (Simon if they are employed
just to see if a patient has a high risk of dying when the attending physician
is unable to change that prognosis. In opposition, we consider a biomarker
useful if they provide additional information to a detailed clinical
evaluation. In the context of infection and sepsis, biomarkers can potentially
provide the following additional information:

1. Screening;

2. Diagnosis;

3. Risk stratification;

4. Monitoring response to therapy; and

5. Antibiotic stewardship.

In this article we discuss recent data on the role of
biomarkers of sepsis, in particular procalcitonin (PCT) and C-reactive protein
(CRP), in the Diagnosis and Antibiotic stewardship.

Diagnosis

Both single as well as serial measurements of biomarkers
have been evaluated in diagnosis, in a variety of infections as well as in
methodologies, namely in inclusion and exclusion criteria, used for the
selection of patients to be evaluated and analysed (Simon clinical settings, namely
emergency departments, medical and surgical wards and intensive care units
(ICUs). However, the results are, at times, contradictory. This is a
consequence of the choice of different methodologies, namely in inclusion and
exclusion criteria, used for the selection of patients to be evaluated and
analysed (Simon et al. 2004; Tang et al. 2007).

In most studies, patients were included if they presented
with SIRS and were subsequently stratified according to the American College of
Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus
Conference criteria into sepsis, severe sepsis and septic shock (Levy et al.
2003). Such methodology could result in an assessment of clinical severity
rather than the evaluation of the diagnostic accuracy of the biomarker in
infection itself. The “gold standard”, which should be presence of documented
infection, that is patients with a defined source of infection with positive
cultures, as opposed to patients with no infection and no antibiotic therapy is
frequently ignored (Cohen et al. 2001). methodologies, namely in inclusion and
exclusion criteria, used for the selection of patients to be evaluated and
analysed (Simon

Several studies have assessed the diagnostic performance of
infection of a single measurement of a biomarker in different clinical settings
and different infections (Table 1). In clinical practice, a markedly elevated
serum level of a biomarker, e.g. CRP levels >5-10 mg/dL, may help to confirm
the diagnosis of sepsis. Concerning PCT, the major limitation in diagnosis is
the frequent finding of patients with documented infections with very low or
even undetectable levels. This is particularly true in infections considered by
the manufacturer to be “localised”, like empyema or abscesses (Christ-Crain et
al. 2010). At the bedside, clinicians
should always consider the possibility of a false-positiv test because
inflammatory stimuli other than bacterial infection can occur in critically ill
patients, particularly during the first 72 hrs of postoperative course and
major trauma. Not withstanding, usually these later conditions are usually
easily diagnosed and identified as causes of biomarker elevations whereas
changes in biomarker concentrations without an obvious reason can usually be
caused by the emergence of infection and sepsis that are frequently silent in
the beginning (Povoa 2008).

Since biomarkers are not static but on the opposite dynamic,
with marked changes in serum concentrations over time, serial measurements
could be more informative. Our group demonstrated that daily CRP determinations
are useful as a marker of infection prediction in ICU patients admitted for
longer than 72 hrs. During the five days before the day of infection diagnosis
CRP showed a steady and significant increase in infected patients, whereas in
noninfected patients CRP remained almost unchanged (Povoa et al. 2006) (Figure
1). Patients, who presented a combination of a maximum daily CRP change higher
than 4.1 mg/dL plus a concentration above 8.7 mg/dL, had an 88% risk of
ICU-acquired infection.

In a cohort of mechanically ventilated patients (Luyt et al.
2008), absolute PCT values as well as its kinetics over five days before
clinical suspicion of pneumonia has been shown to have poor diagnostic accuracy
for ventilator associated pneumonia (VAP) (AUC 0.51 and 0.62, respectively).
More recently, two studies found that the diagnostic value of PCT to assess
early onset pneumonia is poor in post-cardiac arrest hypothermia patients. In one
study (Schuetz et al. 2010), PCT showed a steady decrease until day seven
without differences in patients with and without presumed infection whereas CRP
was significantly more elevated in patients with pneumonia.

Antibiotic Stewardship

The decision to start and stop antibiotics is probably one
of the most frequent and difficult decisions at the bedside. In addition, the
recommended durations of antibiotic therapy of the majority of infections are
not based on data from randomised trials.

Two studies have demonstrated in VAP, that the
implementation of a discontinuation antibiotic policy (Micek et al. 2004) as
well as a fixed antibiotic duration (Chastre et al. 2003) could significantly
decrease the duration of antibiotic therapy to 6 and 8 days, respectively, in
comparison to traditional and longer antibiotic durations of the control
groups, 8 and 15 days, respectively, without any differences in outcome. It is
important to emphasise that both studies were conducted without the use of
biomarkers!

Several original trials showed that the use of PCT in
different infections, lower respiratory tract infection, acute exacerbation of
chronic bronchitis, community-acquired pneumonia (Christ-Crain et al. 2006) and
VAP (Stolz et al. 2009), could safely decrease the rate of antibiotic
prescription and the duration antibiotic therapy. However, these analyses were
markedly biased by the very long antibiotic therapies of the controls. In
ProCAP (Christ-Crain et al. 2006), ProHOSP (Schuetz et al. 2009) and ProVAP
(Stolz et al. 2009) trials, the control groups were on antibiotics for 12, 10
and 15 days, respectively!

In the ICU setting, several trials have been recently
published assessing the role of PCTguided antibiotic therapy (Bouadma et al.
2010; Hochreiter et al. 2009; Jensen 2009; Nobre et al. 2008). With one
exception (Jensen 2009), PCT-guided group showed a significantly lower duration
of antibiotic therapy and smaller antibiotic exposure. However, there are
several caveats in these studies that need to be discussed. In two trials
(Hochreiter et al. 2009; Nobre et al. 2008), more than 70 percent of the
eligible patients were excluded for reasons that were difficult to accept since
they are common in ICU setting, namely Pseudomonas aeruginosa infection. In the
PRORATA trial, there were significant rates of protocol violations in the
PCT-guided group (Bouadma et al. 2010). In 71.2 percent of the episodes of
clinical decision, the attending physicians did not follow PCT-guided
recommendations for several reasons. At inclusion, 69 infected patients had
PCT<0.5μg/L, but in 94 percent the attending physician prescribed
antibiotics against the recommendations. In follow-up, antibiotics were stopped
in 39 pts with PCT>0.5μg/L, since they were considered clinically cured also
against the recommendations; in 111 patients, antibiotics were maintained even
after discharge (N=32) and in 79 unstable patients despite a PCT<0.5μg/L
(Bouadma et al. 2010) Finally, two trials (Bouadma et al. 2010; Jensen et al.
2009) demonstrated that patients from the PCT-guided groups presented more
organ dysfunction and failure, in particular late failure.

In a pragmatic, 2x2 factorial, cluster randomised trial in
which two interventions were tested,availability of a CRP test and/or training
in communication skills, clearly showed that availability of a CRP test could
significantly decrease antibiotic prescription (Cals et al. 2009). This result
is noteworthy since this study was performed in The Netherlands, which is the
European country with the lowest antibiotic prescription in the community.

Conclusions

The ideal biomarker has not yet been identified.
Unfortunately, multiple biomarkers correlate only with mortality and few add
additional valuable information that can be useful in the clinical decision
making process at the bedside. Among all known biomarkers probably PCT and CRP
are those with more solid data. Is it time yet to use biomarkers in sepsis? The
answer is clearly yes but NEVER to be used solely, always in conjunction with a
complete clinical evaluation and with a perfect knowledge of its biology,
strengths and limitations.

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